Chapter Two - Hematopoietic Stem Cell Development: An Epigenetic Journey

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Abstract

Hematopoietic development and homeostasis are based on hematopoietic stem cells (HSCs), a pool of ancestor cells characterized by the unique combination of self-renewal and multilineage potential. These two opposing forces are finely orchestrated by several regulatory mechanisms, comprising both extrinsic and intrinsic factors. Over the past decades, several studies have contributed to dissect the key role of niche factors, signaling transduction pathways, and transcription factors in HSC development and maintenance. Accumulating evidence, however, suggests that a higher level of intrinsic regulation exists; epigenetic marks, by controlling chromatin accessibility, directly shape HSC developmental cascades, including their emergence during embryonic development, maintenance of self-renewal, lineage commitment, and aging. In addition, aberrant epigenetic marks have been found in several hematological malignancies, consistent with clinical findings that mutations targeting epigenetic regulators promote leukemogenesis. In this review, we will focus on both normal and malignant hematopoiesis, covering recent findings that illuminate the epigenetic life of HSCs.

Introduction

Hematopoiesis is the highly dynamic process sustaining the life-long production of blood, one of the most highly regenerative tissues. All hematopoietic lineages—including erythrocytes, platelets, myelocytes, and lymphocytes—derive from a pool of multipotent hematopoietic stem cells (HSCs) residing in the bone marrow (BM). HSCs are characterized by their ability to both self-renew and differentiate: while self-renewal guarantees the life-long maintenance of the stem cell compartment, differentiation involves the sequential steps leading to the production of mature blood cells.

Multilineage hematopoietic stem and progenitor cells (HSPCs) emerge early in ontogeny. After a first wave of primitive blood cells arising from the mesoderm, multilineage HSCs start to emerge from the extraembryonic yolk sac and placenta, followed by the aorta-gonad-mesonephros (AGM) region of the embryo (Moore and Metcalf, 1970, Samokhvalov et al., 2007). As gestation progresses, HSCs migrate to the fetal liver, which becomes the major site of definitive hematopoiesis until the latest stages of embryonic development. Shortly before birth, blood cell production emerges in the BM, the final and predominant site of hematopoiesis throughout adulthood (Fig. 2.1A) (Lux et al., 2008). In adult mammals, definitive hematopoiesis is sustained by a pool of long-term HSCs (LT-HSCs), from which short-term HSCs (ST-HSCs) and multipotent progenitors (MPPs) are derived; these stem and progenitor cells present a progressively decreased self-renewal potential, but still hold a multipotential differentiation capacity. Downstream of MPPs are lineage-restricted progenitors, responsible for generating a large pool of terminally differentiated cells eventually released into the peripheral blood (Fig. 2.1B).

Several factors, both extrinsic and intrinsic, regulate the progression of HSCs through the different phases of their development. Cell-extrinsic cues are provided by the stem cell niche and include cytokines, growth factors, chemokines, oxygen tension, and nutrients (Smith and Calvi, 2013, Suda et al., 2011, Wilson and Trumpp, 2006). These signals merge into a network of intrinsic regulators, comprising signaling pathways, transcription factors, and epigenetic marks. By controlling chromatin conformations and accessibility, epigenetic mechanisms tune the expression of genes involved in HSC development and help orchestrate the balance between stemness and lineage commitment. Over the past decade, analyses of knockout (KO) mice have contributed to unveiling a number of genes vital for HSC development and function (Rossi et al., 2012), including, but not limited to: DNA-methylating enzymes, Polycomb-Group (PcG) complexes, histone modifiers, and factors involved in microRNA synthesis (summarized in Table 2.1, Table 2.2, Table 2.3, Table 2.4). Deletion of these genes in KO mice has been associated with a variety of phenotypes—from hematopoietic failure and repopulation defects to hyperproliferation and leukemia—reinforcing the hypothesis that epigenetic marks concur to mold developmental programs in HSCs. In this review, we will illustrate how epigenetic regulators contribute to the different stages of HSC development—from their embryonic emergence to adult life—focusing on the mechanisms that contribute to HSC self-renewal, lineage commitment, aging, and leukemogenesis.

Section snippets

Principles of Epigenetic Regulation

Epigenetic marks include DNA methylation, covalent histone modification, and chromatin remodeling. In addition to these mechanisms, microRNAs and long noncoding RNAs (lncRNAs) have recently emerged as important regulators of transcriptional and epigenetic programs, playing a pivotal role in early development, lineage specification, and differentiation. In this review, we will focus mainly on DNA and chromatin modifications; for a detailed description of microRNA and lncRNA in hematopoietic

DNA methylation

The importance of proper DNA methylation throughout mammalian development is made evident by germline deletion of Dnmts: Dnmt1-null mice die at gastrulation (Li, Bestor, & Jaenisch, 1992), Dnmt3b-null mice die at roughly E9.5, and Dnmt3a-null mice die at roughly 3 weeks of age (Okano, Bell, Haber, & Li, 1999). Additional research has shown DNA methylation to be remarkably fluid early in development: present in gametes, nearly completely erased in the early morula, and then largely reestablished

Role of Epigenetic Regulators in Hematopoietic Malignancies

Despite the intense regulatory activity presiding over hematopoietic homeostasis, aberrant clones may arise from HSPCs, giving rise to a pool of malignant cells characterized by unrestrained proliferation and/or abnormal differentiation patterns. Previously viewed as exquisitely genetic diseases, hematopoietic malignancies have now emerged as a deviant developmental process. As such, leukemogenesis can be ascribed to the abnormal activity of the same regulatory mechanisms modulating

Conclusions

Over the past decade, the understanding of the molecular mechanisms presiding over epigenetic regulation has greatly improved. Not only have epigenetic marks emerged as pivotal regulators of the different stages of hematopoietic development but they also appear to be key players in leukemogenesis. In the future, the ability to manipulate the epigenetic pattern of genes involved in hematological diseases is expected to provide a huge array of new therapeutic approaches for leukemia. Along this

Acknowledgments

The authors would like to thank members of the Goodell lab for helpful discussions. The authors are supported by grants DK092883, 5T32HL092332, 1RC2AG036562-01, the Samuel Waxman Foundation, and the Cancer Prevention and Research Institute of Texas (CPRIT RP110028). L. R. was supported by the Italian Leukemia and Lymphoma Association, section of Bologna (BolognaAIL).

References (123)

  • S.Y. Jo et al.

    Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation

    Blood

    (2011)
  • L.M. Kamminga et al.

    The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion

    Blood

    (2006)
  • K.P. Koh et al.

    Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells

    Stem Cell

    (2011)
  • H.J. Lawrence et al.

    Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis

    Blood

    (1997)
  • E. Li et al.

    Targeted mutation of the DNA methyltransferase gene results in embryonic lethality

    Cell

    (1992)
  • Z. Li et al.

    Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies

    Blood

    (2011)
  • Z. Li et al.

    Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex

    The Journal of Biological Chemistry

    (2006)
  • D.C. Liang et al.

    Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A

    Blood

    (2013)
  • C.T. Lux et al.

    All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac

    Blood

    (2008)
  • J. Maes et al.

    Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells

    Blood

    (2008)
  • I.J. Majewski et al.

    Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells

    Blood

    (2010)
  • R. Marmorstein et al.

    Histone modifying enzymes: Structures, mechanisms, and specificities

    Biochimica et Biophysica Acta

    (2009)
  • K.A. McMahon et al.

    Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal

    Cell Stem Cell

    (2007)
  • K.H. Metzeler et al.

    ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN favorable genetic category

    Blood

    (2011)
  • K. Moran-Crusio et al.

    Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

    Cancer Cell

    (2011)
  • R.M. O’Connell et al.

    MicroRNAs and hematopoietic cell development

    Current Topics in Developmental Biology

    (2012)
  • H. Oguro et al.

    Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmi1

    Stem Cell

    (2010)
  • M. Okano et al.

    DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development

    Cell

    (1999)
  • T. Okuda et al.

    AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis

    Cell

    (1996)
  • K. Orford et al.

    Differential H3K4 methylation identifies developmentally poised hematopoietic genes

    Developmental Cell

    (2008)
  • R.L. Piekarz

    Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: A case report

    Blood

    (2001)
  • L.M. Pillay et al.

    The Hox cofactors Meis1 and Pbx act upstream of gata1 to regulate primitive hematopoiesis

    Developmental Biology

    (2010)
  • C. Quivoron et al.

    TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis

    Cancer Cell

    (2011)
  • J. Roman-Gomez et al.

    5′ CpG island hypermethylation is associated with transcriptional silencing of the p21CIP1/WAF1/SDI1 gene and confers poor prognosis in acute lymphoblastic leukemia

    Blood

    (2002)
  • L. Rossi et al.

    Less is more: Unveiling the functional core of hematopoietic stem cells through knockout mice

    Cell Stem Cell

    (2012)
  • A.E. Smith et al.

    Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value

    Blood

    (2010)
  • O. Abdel-Wahab et al.

    Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms

    Leukemia

    (2011)
  • O. Abdel-Wahab et al.

    DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms

    Leukemia

    (2011)
  • A. Aggerholm et al.

    Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients

    European Journal of Haematology

    (2006)
  • F. Antequera et al.

    Number of CpG islands and genes in human and mouse

    Proceedings of the National Academy of Sciences of the United States of America

    (1993)
  • A.J. Bannister et al.

    Regulation of chromatin by histone modifications

    Cell Research

    (2011)
  • A. Batova et al.

    Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia

    Cancer Research

    (1997)
  • R. Bejar et al.

    Clinical effect of point mutations in myelodysplastic syndromes

    New England Journal of Medicine

    (2011)
  • S.L. Berger

    The complex language of chromatin regulation during transcription

    Nature

    (2007)
  • U. Bissels et al.

    MicroRNAs are shaping the hematopoietic landscape

    Haematologica

    (2012)
  • M.T. Bocker et al.

    Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging

    Blood

    (2011)
  • M. Brecqueville et al.

    Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms

    Genes, Chromosomes and Cancer

    (2012)
  • A.-M. Bröske et al.

    DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction

    Nature Genetics

    (2009)
  • V. Calvanese et al.

    A promoter DNA demethylation landscape of human hematopoietic differentiation

    Nucleic Acids Research

    (2011)
  • R. Cao et al.

    Role of histone H3 lysine 27 methylation in Polycomb-group silencing

    Science

    (2002)
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